The objective of our investigations is to develop the hypothesis that the glycosylation reaction responsible for the production in vivo of hemoglobin AIc is occurring with other body proteins which are leading to altered function and the development of the complications associated with diabetes mellitus. Biological studies have shown that hemoglobin AIc is formed from hemoglobin A as a postsynthetic modification whose rate is dictated by the environment in which the red cells circulate. During the past year it has been possible to show that glucose-6-phosphate nonenzymatically forms an adduct with hemoglobin A, possibly hemoglobin AIb, which could then subsequently be dephosphorylated to form hemoglobin AIc. It is proposed that the aldehyde of the carbohydrate forms a Schiff base adduct with the amino terminal valine of the beta chain of hemoglobin which subsequently undergoes an Amadori rearrangement. The addition of glucose-6-phosphate to hemoglobin is an especially attractive mechanism since the phosphate would allow the orientation and stabilization of the sugar in the DPG pocket of the hemoglobin molecule thus explaining the specificity of the reaction for the amino terminus of the beta chain. In fact it is possible nonenzymatically to form hemoglobin adducts with a number of glycolytic intermediates; glyceraldehyde-3-phosphate, fructose-6-phosphate. The two pre-requisites necessary for adduct formation is the presence of a phosphate an aldehyde or a ketone functionality. The increased intracellular concentration of glucose-6-phosphate in the red cells of diabetic adds further support for this pathway. We have extended our studies to glycosylation of hemoglobin to a biochemically similar tissue, the lens. Studies underway have shown that they glycosylation of crystallin proteins leads to an increased susceptibility to sulfhydryl oxidation and the formation of high molecular weight aggregates which imparts an opacity to the solutions mimicking diabetic cataracts formed in vivo. The biochemical analyses of this phenomena are currently underway.